Valaciclovir – a first line antiviral medicine

Valaciclovir is an antiviral medicine which can be used for the treatment of Herpes simplex infections and herpes zoster. As of 1 March, 2016, Special Authority approval is no longer required. Valaciclovir is as effective as aciclovir across the same range of indications, and has a simpler dosing regimen which may improve patient adherence.

Valaciclovir is now available without restriction

Valaciclovir and aciclovir are antiviral medicines that interfere with replication of Herpes viruses including Herpes
simplex and Varicella zoster.1 General practitioners in New Zealand are more likely to be familiar with aciclovir
than valaciclovir as it has been fully subsidised and used in clinical practice for longer.

Valaciclovir consists of a valine amino acid attached to an aciclovir molecule. Following administration, the amino
acid is cleaved and valaciclovir is converted into aciclovir. Due to increased bioavailability oral valaciclovir can be
taken less frequently than oral aciclovir, e.g. two to three times daily instead of five times daily.2, 3

Prior to 1 March, 2016, Special Authority approval was required for patients to receive subsidised treatment with valaciclovir,
500 mg tablets; the Special Authority criteria has been removed and valaciclovir is now available without restriction
for:

The treatment of first and recurrent episodes of genital herpes

Suppression of genital herpes recurrences

The treatment of herpes zoster

This article provides clinical guidance for the use of valaciclovir in patients with each of these conditions.

Prescribing valaciclovir

Dosing and duration of treatment

The recommended doses, frequency and duration of valaciclovir treatment differ according to the condition being treated.
For prescribing information refer to the specific conditions below or to the New Zealand Formulary (NZF).

Adverse effects and cautions for prescribing

The adverse effects most commonly experienced by patients taking valaciclovir are headaches, rhinitis and flu-like symptoms.
These symptoms are usually mild to moderate, although some patients may discontinue treatment as a result. In randomised
controlled trials the incidence of these symptoms is only slightly higher than in patients taking placebo.4, 5

Patients taking valaciclovir should be advised to maintain adequate hydration. There have been isolated case reports
of older patients or patients with severely reduced renal function developing acute kidney injury following treatment
with 1 g three times daily, for as little as one day.6, 7

Rarely, valaciclovir use can cause aciclovir-induced neurotoxicity.6 Symptoms of aciclovir-induced neurotoxicity
include hallucinations, involuntary movements and characteristic delusions of death: either that the patient or someone
else is going to die or has already died.8 Withdraw treatment in patients suspected of having aciclovir-induced
neurotoxicity, especially if they have reduced renal function.8

Dose adjustments are required for some patients

Reduced dosing is required in patients with renal impairment. Dose adjustments are required in patients with renal impairment,
as the half-life of valaciclovir is extended from two to three hours in healthy individuals, up to 14 hours in patients
with end-stage renal failure.1, 8

Valaciclovir for the treatment of genital herpes

Without treatment the symptoms of genital herpes can last for up to three weeks.3 Treatment with valaciclovir
or aciclovir reduces the time to healing, the severity and duration of symptoms and viral shedding.1 In one
large randomised controlled trial the median time to symptom resolution for patients taking either valaciclovir or aciclovir
was approximately nine days; with almost all patients having symptom resolution and lesion healing by two weeks.10

Oral valaciclovir, 1000 mg, twice daily, produces the same clinical benefit as oral aciclovir, 200 mg, five times daily,
when taken for the same duration, with similar duration of symptoms, pain, viral shedding and time to healing.10

Continuous valaciclovir treatment can reduce the incidence of symptomatic episodes

Patients who regularly experience recurrent genital herpes, e.g. six episodes or more per year, may trial
preventative treatment to reduce the impact of the disease and to provide a sense of control over the disease
process.3,
11 There is evidence that continuous treatment with valaciclovir can reduce the number of recurrent episodes of
genital herpes by approximately 60%.11 The clinical threshold at which continuous treatment with valaciclovir
could be offered is influenced by the patient’s ability to tolerate recurrences and their willingness to adhere
to treatment.9

How to prescribe valaciclovir for the treatment of genital herpes

For first episodes: valaciclovir 500 mg, twice daily, for seven days,), or longer if new lesions
appear or lesions are not fully healed (consider 1000 mg, twice daily, for seven to ten days in immunocompromised patients)

Withdraw treatment every 6–12 months to reassess the recurrence frequency; consider restarting treatment after two
recurrences

Dosing may be increased to 500 mg, twice daily, or 1 g, once daily, for patients who continue to experience multiple
recurrences (unapproved dose)

* Valaciclovir doses in this article may differ from those in the Medicine Data Sheet and the NZF. This
dosing information is endorsed by the New Zealand Herpes Foundation.

Valaciclovir for pregnant women, or women planning pregnancy

Transmission of the herpes virus to neonates during delivery is a potentially serious event. Women who have had symptomatic
herpes before pregnancy can be assured that the risk of passing the infection on to their baby is very small (approximately
0.05%), if they have no signs or symptoms at the time of delivery.3 Suppressive therapy to avoid a recurrence
near the time of delivery can be considered in women with a history of genital herpes; consultation with an obstetrician
or gynaecologist is recommended.3

The greatest risk of neonatal transmission occurs when a woman has a first episode of symptomatic herpes near or at
the time of delivery. For women who develop symptomatic genital herpes during pregnancy, particularly during
the third trimester, consultation with an obstetrician or gynaecologist is recommended. For women who develop
symptomatic genital herpes during the first or second trimester, standard treatment with antiviral medicines
and vaginal delivery is possible. Delivery by caesarean section is recommended for women with a first episode
during the third trimester.3 A
first episode of herpes symptoms during pregnancy may not be a new infection, due to changes in immune function,
this may be the first symptomatic episode in a woman previously infected.3

If a pregnant woman, without a prior history of symptomatic genital herpes, has a partner with a history of herpes
symptoms, serological testing of both partners may be beneficial. If the male partner is seropositive for HSV-2
infection and the female seronegative, suppressive treatment of the male partner could reduce the risk of transmission;
this regimen has been shown to reduce the risk of transmission between partners by approximately 50%.3, 9 The
use of valaciclovir to prevent transmission in this way is an unapproved indication.

Advice for patients with genital herpes 3, 9, 13

Inform patients that there is no cure for herpes virus infection; valaciclovir can reduce the severity of symptoms and
the incidence of recurrences, but does not clear the infection.

Transmission risk is highest during recurrences and patients should avoid sexual contact while they have symptoms, even
if they are taking valaciclovir. Transmission can also occur when people are asymptomatic. Infected people will need to
discuss the approach they wish to take if they want to avoid transmission to an uninfected partner; condoms can reduce
but not eliminate the risk of transmission.

Herpes recurrences may be preceded by symptoms such as tingling, burning or pain in the anogenital region, which may
extend to hips or legs for two to five days before visible lesions develop. Patients should begin taking valaciclovir
to treat a recurrence at the onset of these symptoms.

Salt baths may relieve pain and improve the healing of lesions, e.g. half a cup of salt in a bath.
Patients often experience pain during urination and application of lignocaine gel a few minutes prior to urination
may lessen discomfort. Topical lignocaine products are not subsidised for this indication. Sensitisation to topical
lignocaine occurs rarely but patients should be aware of the possibility of irritant hypersensitivity.

The role of testing in the diagnosis and treatment of genital herpes

Testing should be requested for patients with first episodes of genital herpes (and atypical recurrences) to confirm
the diagnosis and determine the type of virus involved. This can provide prognostic information, e.g. HSV-2 is
associated with more frequent recurrences of genital herpes than HSV-1 infections. Approximately 70–90%
of patients who have symptomatic HSV-2 genital infections and 20–50% of patients with genital HSV-1 infections
experience a recurrence within the first year.12

After removing the covering tissue with a needle or scalpel, swabs are taken from the base of the lesion to collect
virus-infected cells and vesicular fluid. Polymerase chain reaction (PCR)-based detection is now the preferred method
for herpes virus testing. If this is not available viral culture is an alternative method of testing; culture has a higher
specificity, but lower sensitivity, than PCR-based detection and usually takes longer to receive a result.

Arrange a follow-up appointment at five to seven days for patients with test results positive for genital herpes to
provide counselling and future lifestyle advice (see: “Advice for patients with genital herpes”).

Herpes virus serology, i.e. testing for the presence of antibodies to HSV-1 or HSV-2, is not recommended as a routine
test. Herpes antibodies typically take two to six weeks to develop and sometimes longer. Patients presenting
with new infections are therefore likely to test negative for antibodies. A positive serology result may indicate
that the patient has previously had an asymptomatic infection but would not change how they are managed. Serology
may be useful in specific circumstances, such as to test whether a pregnant woman has antibodies to herpes virus
if their partner develops symptomatic genital herpes during the pregnancy (see: “Valaciclovir for
pregnant women, or women planning pregnancy”).3

Valaciclovir for the treatment of herpes zoster (shingles)

Herpes zoster, also known as shingles, is caused by reactivation of latent Varicella zoster virus in individuals who
have previously had varicella, and usually occurs in people aged 40 years and over.14

Patients with herpes zoster often describe an itching or burning, shooting pain which precedes a characteristic rash
by three to four days. Typically, patients display a unilateral rash with a distribution corresponding to the affected
dermatome.14 Diagnosis can usually be made on the basis of this dermatomal rash with accompanying pain, without
the need for further investigation. Testing may be necessary if there is uncertainty, e.g. to differentiate between Herpes
simplex infection and herpes zoster or if herpes zoster without rash (zoster sine herpete) is suspected.

Post-herpetic neuralgia occurs in 10–18% of patients with herpes zoster and causes ongoing pain after the resolution
of other symptoms and signs.14

Valaciclovir is more effective at reducing pain due to herpes zoster than aciclovir

Antiviral medicines reduce the severity and duration of acute pain for patients with herpes zoster; valaciclovir may
result in improved symptoms compared with the use of aciclovir. A study of over 1,000 patients, using comparable doses
of valaciclovir or aciclovir, reported that resolution of pain was on average 25% quicker for patients taking valaciclovir
than patients taking aciclovir (p=0.001). The duration of cutaneous symptoms and signs was similar for both groups of
patients.15

Valaciclovir is unlikely to prevent post-herpetic neuralgia, as this has not been observed in studies of aciclovir for
the treatment of herpes zoster, although clinical trials assessing this end-point with valaciclovir have not been conducted.16

How to prescribe valaciclovir for the treatment of herpes zoster:17

Valaciclovir, 1g, three times daily, for seven days to reduce the pain associated with symptomatic episodes; lower
doses are required in patients with reduced renal function, see: www.nzf.org.nz/nzf_3443

Immunocompromised patients should continue dosing for at least two days after lesions have crusted, which may result
in treatment for longer than seven days

Red flag: Patients with herpes zoster and signs of involvement of the ophthalmic branch of the trigeminal
nerve (herpes zoster ophthalmicus) should be discussed with an ophthalmologist.18 Herpes zoster ophthalmicus
can result in serious sequelae including keratitis, uveitis, glaucoma and blindness.2

Advice for patients with herpes zoster

Advise patients with herpes zoster to avoid physical contact with others to reduce the risk of transmission, especially
infants aged one year and under, pregnant women and immunocompromised people. Lesions should be kept clean and dry and
can be covered with a dressing without an adhesive backing.2 Patients should refrain from scratching the
rash to reduce transmission and scarring.

Following the resolution of cutaneous symptoms and signs patients may experience ongoing pain that may resolve over
months to years, but can often continue despite treatment.19 In clinical trials in patients with post-herpetic neuralgia,
fewer than half of patients treated with analgesia have a 50% or greater reduction in pain.19 Treatment options
in primary care for chronic pain due to herpes zoster include topical capsaicin creams (0.075%), paracetamol, or for more
severe pain, medicines such as tricyclic antidepressants or anticonvulsants may be of benefit.20

Vaccination reduces the risk of developing herpes zoster

Zoster vaccine (Zostavax, a live attenuated vaccine) is recommended but not subsidised in New Zealand for people aged
50 years and over.14

Vaccination can prevent the development of herpes zoster by approximately 50% and reduce the incidence of post- herpetic
neuralgia by approximately 40%.21, 22 Patients aged 60–69 years may receive a greater benefit from vaccination
(64% reduction in risk) than patients aged 70 years and over (36% reduction in risk).21 The number-needed-to-treat
is 50, in patients aged 60 years and over, for vaccination to prevent one case of herpes zoster. Adverse effects
include mild to moderate injection site reactions.21 The vaccine is effective for at least five years,
but it is not known how long protection lasts beyond this time and if, or when, repeat vaccination is necessary.14

Problematic cold sores (herpes labialis)

Most patients with herpes labialis experience no more than one recurrence per year, although 5–10% of patients experience
six or more episodes per year.23 The majority of patients who have recurrences will have episodes that are
not sufficiently problematic for them to seek medical attention. Triggers for recurrence include sun exposure, stress,
hormonal fluctuations and minor trauma or cosmetic procedures.23

For patients who present with particularly painful or extensive cold sores, clinicians may advise the use of a topical
product containing aciclovir (available unsubsidised in pharmacies and supermarkets) or consider prescribing oral valaciclovir:

Topical aciclovir 5% creams have been shown to produce statistically significant but clinically small effects in patients
with cold sores, reducing pain and symptoms by approximately half a day.24

Oral valaciclovir, 2 g twice daily for one day, reduces healing time by approximately one day.24 However,
this is an unapproved use of oral valaciclovir.17

There is little evidence to support the use of antiviral medicines to prevent recurrences of cold sores in patients
without underlying conditions, e.g. immunocompromised patients.23 For patients with recurrent cold sores,
wearing sunscreen on the affected area during periods of remission may reduce recurrences.23 Stress management
techniques may also be beneficial as recurrence of cold sores has been associated with periods of psychological stress.
Recent research has identified a molecular mechanism by which stress signals in neurons can induce reactivation of the
Herpes virus.25

Acknowledgement

Thank you to Associate Professor Lance Jennings, Clinical Virologist, University of Otago, Christchurch and Canterbury
Health Laboratories, Canterbury DHB, and Dr John Taylor, Senior Lecturer, Biological Sciences, University of
Auckland for expert review of this article.